Receptors to chemical transmitter substances exist not only on the input component of the neuron, the cell body and dendrites, but also on the output component, the presynaptic terminals. Unlike the receptors on the cell body and dendrites, presynaptic receptors do not control the firing of the neuron, but modulate the ability of the action potential in the presynaptic terminal to release transmitter. Presynaptic modulation, as exemplified by presynaptic inhibition and facilitation, is therefore a particularly well-documented instance of a local circuit interaction. Presynaptic facilitation is a particularly important form of local circuit modulation because it serves as a short-term memory mechanism for behavioral sensitization, a simple form of learning in the marine snail Aplysia. Physiological and pharmacological studies in Aplysia suggest that presynaptic facilitation is mediated by putative serotonergic neurons and produces its action on transmitter release by acting through cyclic AMP. Since this preparation is particularly suitable for relating cyclic nucleotide biochemistry to synaptic function and behavior, we propose to explore the biochemical mechanisms underlying this form of modulation by examining four interrelated questions: 1) Are the facilitator neurons actually serotonergic? 2) Does the presynaptic facilitator cell increase the endogenous level of cAMP in the terminal of the presynaptic neurons? 3) Is phosphorylation of membrane proteins involved in presynaptic facilitation and, more specifically, is Ca+2-channel phosphorylation the molecular mechanism underlying the local enhancement of transmitter release? and 4) Does the Ca+2-dependent regulator protein participate in the long-term expression of presynaptic facilitation?